GPR40 is necessary but not sufficient for fatty acid stimulation of insulin secretion in vivo

被引:224
作者
Latour, Martin G.
Alquier, Thierry
Oseid, Elizabeth
Tremblay, Caroline
Jetton, Thomas L.
Luo, Jian
Lin, Daniel C. -H.
Poitout, Vincent
机构
[1] Univ Montreal, Ctr Hosp, Ctr Rech, Montreal Diabet Res Ctr, Montreal, PQ H1W 4A4, Canada
[2] Pacific NW Res Inst, Seattle, WA USA
[3] Univ Vermont, Coll Med, Div Endocrinol Diabet & Metab, Burlington, VT USA
[4] Amgen Inc, San Francisco, CA USA
[5] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada
[6] Univ Montreal, Dept Nutr, Montreal, PQ H3C 3J7, Canada
[7] Univ Montreal, Dept Biochem, Montreal, PQ H3C 3J7, Canada
基金
加拿大健康研究院;
关键词
PANCREATIC BETA-CELL; RECEPTOR GPR40; GLUCOSE; MECHANISMS; RELEASE; IDENTIFICATION; LIPOTOXICITY; INFUSION; GLUCAGON; KINASE;
D O I
10.2337/db06-1532
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Long-chain fatty acids amplify insulin secretion from the pancreatic beta-cell. The G-protein-coupled receptor GPR40 is specifically expressed in beta-cells and is activated by fatty acids; however, its role in acute regulation of insulin secretion in vivo remains unclear. To this aim, we generated GPR40 knockout (KO) mice and examined glucose homeostasis, insulin secretion in response to glucose and Intralipid in vivo, and insulin secretion in vitro after short- and long-term exposure to fatty acids. Our results show that GPR40 KO mice have essentially normal glucose tolerance and insulin secretion in response to glucose. Insulin secretion in response to Intralipid was reduced by similar to 50%. In isolated islets, insulin secretion in response to glucose and other secretagogues was unaltered, but fatty acid potentiation of insulin release was markedly reduced. The G alpha(q/11) inhibitor YM-254890 dose-dependently reduced palmitate potentiation of glucose-induced insulin secretion. Islets from GPR40 KO mice were as sensitive to fatty acid inhibition of insulin secretion upon prolonged exposure as islets from wild-type animals. We conclude that GPR40 contributes approximately half of the full acute insulin secretory response to fatty acids in mice but does not play a role in the mechanisms by which fatty acids chronically impair insulin secretion.
引用
收藏
页码:1087 / 1094
页数:8
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